JAK-STAT signaling activated by Abl oncogenes

The Abl oncoproteins v-Abl and BCR-Abl can activate member of the signal tr ansducers and activators of transcription (STAT) family of signaling protei ns. The mechanisms by which these oncoproteins activate STATs appear to dif fer, In cells transformed by v-Abl, Janus kinase (JAK) tyrosine kinases are constitutively activated. Tn these cells, the v-Abl oncoprotein and the JA K kinases physically associate. Mapping of the JAK interaction domain in v- Abl demonstrates that amino acids within the carboxyl terminal region of v- Abl bind JAKs through a direct interaction. A mutant of v-Abl lacking this region does not bind or activate JAK 1 in vivo, fails to activate STAT prot eins, does not induce cellular proliferation, and is less efficient in cell ular transformation. Kinase inactive mutants of JAK 1 inhibit the ability o f v-Abl to activate STATs, to induce cytokine-independent proliferation, an d to transform bone marrow cells. Interestingly, these effects correlate wi th defects in the activation of several pathways by v-AbI including Akt, PI 3-kinase, STATs, and Ras, These data suggest that Jak kinases may play an i mportant role in v-Abl induced transformation.